The Emerging and Diverse Roles of Bis(monoacylglycero) Phosphate Lipids in Cellular Physiology and Disease

Abstract

Although understudied relative to many phospholipids, accumulating evidence suggests that bis(monoacylglycero)phosphate (BMP) is an important class of regulatory lipid that plays key roles in lysosomal integrity and function. BMPs are rare in most mammalian tissues, comprising only a few percent of total cellular lipid content, but are elevated in cell types such as macrophages that rely heavily on lysosomal function. BMPs are markedly enriched in endosomal and lysosomal vesicles compared to other organelles and membranous structures, and their unique sn-1:sn-1′ stereoconfiguration may confer stability within the hydrolytic lysosomal environment. BMP-enriched vesicles serve in endosomal-lysosomal trafficking and function as docking structures for the activation of lysosomal hydrolytic enzymes, notably those involved in the catabolic breakdown of sphingolipids. BMP levels are dysregulated in lysosomal storage disorders, phospholipidosis, metabolic diseases, liver and kidney diseases and neurodegenerative disorders. However, whether BMP alteration is a mediator or simply a marker of pathological states is unclear. Likewise, although BMP acyl chain composition may be altered with disease states, the functional significance of specific BMP species remains to be resolved. Newly developed tools for untargeted lipidomic analysis, together with a deeper understanding of enzymes mediating BMP synthesis and degradation, will help shed further light on the functional significance of BMPs in cellular physiology and pathology.

Progranulin deficiency results in reduced bis(monoacylglycero)phosphate (BMP) levels and gangliosidosis

“…Because the levels of the enzymes that catabolize gangliosides were not changed in PGRN-deficient cells or tissues, and because lysosomes appeared mostly intact and functioning, we searched for another cause for gangliosidosis. BMP plays a crucial role in GSL and ganglioside degradation in lysosomes 17 , and its levels are altered in many lysosomal storage diseases 18 . BMP is found in intralumenal lysosomal vesicles (ILVs) where its negatively charged phosphate headgroup may enable binding of lysosomal hydrolases 19,20 .…”

Multi-Omics Analysis of Microglial Extracellular Vesicles From Human Alzheimer’s Disease Brain Tissue Reveals Disease-Associated Signatures

“…We also found a significant increase in the major bis(monoacylglycerol)phosphate (BMP) and monohexosylceramide (MhCer) lipid species ( Figures 4G,H ). An increase of this species of BMP, a lysosome-specific lipid, suggests increased lysosomal lipid content in AD microglia ( Showalter, et al, 2020 ). Elevated levels of MhCer may play a role in microglial activation and immune response ( Brennan, et al, 2017 ; Miltenberger-Miltenyi, et al, 2020 ; Niimura et al, 2010 ), as well as be a precursor of more complex gangliosides ( Merrill, 2011 ).…”

ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling

“…The increase of di-22:6-BMP in whole cell lysate was confirmed by a quantitative mass spectrometry assay specifically designed to assess this lipid (Figure 2D). Moreover, di-18:1-BMP, which appears to be the most abundant species in HeLa cells and is a major species in most human tissues (Showalter et al, 2020) was decreased (Figure 2D). This is consistent with our findings that total PG/BMP species are decreased by about half in VPS13C KO lysosomes, revealing an overall decrease in total BMP but a specific increase in di-22:6-BMP (Figure 2C and S2D).…”